Guest speaker says gender differences underplayed in genetic research

March 24, 2014

David Page, MD: ‘I see an opportunity now to get serious about the biology of X and Y chromosomes.’

There are two types of people in the world — males and females — and for decades gender differences have fueled the growth of many professions, from comics to divorce attorneys to counselors. David C. Page, MD, thinks those differences also should drive the growth of basic scientists.

Scientists are making great strides in advancing the molecular knowledge of humans to develop gene-based medical treatments. But Dr. Page thinks they could do even more by using the research tools they have developed to learn more about the biological differences between males and females.

“Something that is just beginning to open up and is relevant for dermatologists —and all physicians — is that there are enormous numbers of diseases outside the reproductive tract that occur at strikingly different severity in one sex or the other,” Dr. Page said in an interview with the Annual Meeting News about his Sunday Plenary Guest Lecture “Rethinking the Pristine X and Rotting Y Chromosomes.”

“Some of these diseases come very close to dermatology because they involve autoimmune disorders, such as lupus and rheumatoid arthritis. These are diseases that show strikingly different frequencies in men and women,” said Dr. Page, director of Whitehead Institute for Biomedical Research, professor of biology at Massachusetts Institute of Technology, and Howard Hughes Medical Institute Investigator. “The reasons for these differences between the sexes is not known, and they are barely studied.

“I want to shine a light on this question of why there are these huge gender disparities in incidence and severity of diseases outside the reproductive tract. It is so common that it is not the exception — it is the rule — but there is very little attention drawn to this question.”

What is known about gender differences is that the X and Y chromosomes were once an identical pair of autosomes, like the other 22 pairs of chromosomes in the human body. Autosome pairs trade genes in a process called “crossing over” to maintain genetic diversity and eliminate problematic gene mutations. However, a segment of the X chromosome stopped crossing over to the Y about 300 million years ago, causing genetic decay in the Y chromosome.

“This story of the X and Y chromosomes evolving from ordinary autosomes receives a lot of treatment in the popular press,” said Dr. Page, who has done significant chromosome research. “It actually was fodder for gender war accounts. Much has been said about the likelihood that the Y chromosome is going to disappear in 150,000 years or 10 million years and is going to take males with it.

“We have utterly dismissed this idea. Ladies, men will be around a while.”

Two years ago, Dr. Page’s research team compared the human Y chromosome with the Y chromosome of the rhesus macaque, also called Old World monkeys. They found very little difference between the gene content of the two species, he said.

“If the rhesus Y and human Y, separated by 30 million years of evolution, are so similar, let’s just forget all this talk about the Y disappearing. There is no evidence,” Dr. Page said. “The Y chromosome seems to be holding its own quite nicely. It is not shrinking. It is not disappearing. I would say most of the scientific world, in the wake of that paper we published two years ago, no longer gives credence to this disappearing Y idea.

“I see an opportunity to get serious about the biology of the X and Y chromosomes and begin to translate into this space where all physicians know the enormous differences in the incidence of severity of several diseases between the sexes.”

Advances in the knowledge of human genetics have given basic scientists the tools to focus on differences between races, ethnic groups, and geographic groups, but more is needed to improve medical outcomes, Dr. Page said.

“We have a tool kit that asks ‘Why is one man at higher risk or lower risk than another man for any given disease?’ or ‘Why is one woman at higher or lower risk than another woman?’” he said. “But today, we have no toolkit to ask ‘Why are men as a group at higher or lower risk than women as a group?’ That question does not receive as much attention because people don’t know how to experimentally ask the question. The disparities are enormous.

“Those medical geneticists who are out tracking down the genetic risk factors almost always overlook what is for many diseases the single largest risk factor, which is ‘Are you a male or a female?’”

For Dr. Page, this harkens back to the early days of the study of anatomy, when the bodies of prisoners — predominanatly men — were studied by physicians.

“It was quite a while until it came to be understood how much the internal anatomy of males and females differed,” Dr. Page said. “Today, at a molecular level we have a similarly unisex view. I suggest that we will need to make up not one unisex molecular inventory, but that we are going to have to come up with a molecular inventory of the female and of the male, and compare them.

“Imagine if we were trying to treat disease in human males and females without knowing there were anatomic differences between the two. Well, that’s what we are doing today at the molecular level.”

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